The Longevity Dividend: The Economic Advantages Of Geroprotective Treatments

Getting your Trinity Audio player ready...

By Sven Bulterijs

Key Points

• In 2025 there will be almost two people over 65 years old for every person under 20 in Japan.
• The medical cost for the treatment of age-related diseases is a huge threat to the solvency of nationalized and privatized health insurance around the world.  
• Social security in the United States has started to run a deficit in 2011.
• Aging is a global problem affecting developed and developing nations alike.
• Treatment of all diseases separately is a paradigm that fails in old age because a new disease quickly replaces the successfully treated previous disease.
• Geroprotective treatments that slow down the aging process have huge potential to improve the health of the elderly population and reduce the economic burden of population aging.

  Introduction   Biological aging is a deleterious, universal (at least within species), progressive, multisystemic process that leads to functional impairments, increased risk of age-related diseases and disabilities, a reduction in the quality of life, and ultimately death (Strehler et al., 1962; Frolkis, 1982; Bulterijs et al., 2015). The exact molecular mechanisms underlying the aging process are still hotly debated but many believe that some combination of the following are involved: telomere shortening, glycation and crosslinking, mitochondrial dysfunction, genetic and epigenetic changes, altered intercellular communication, loss of proteostasis, accumulation of senescent cells, and stem cell depletion (Sjöberg and Bulterijs, 2009; López-Otín et al., 2013).   An economic burden The factors influencing the economic cost of aging are summarized in figure 1. Over the last century the life expectancy at age 65 has considerably increased from 11.3 years in 1900 to about 15.7 years in 1999 for males (for females it increased from 12.0 years in 1999 to 18.9 years in 1999) (fig. 2; Bell and Miller, 2002). This increase in the length of the period of old age leads to higher costs from (i) medical treatment for age-related diseases, (ii) assistance with daily activities and institutionalized care, and (iii) the cost of pension plans. The aging of the population (demographic aging) impairs the ability of society to bear the cost of aging (fig. 3). The reason for this is that demographic aging increases the dependency ratio, that is, the ratio of those who do not participate in the labor force (the dependent part) and those who participate in the labor force (the productive part). Demographic aging is driven by two main factors, firstly the decrease in fertility (fig. 4) and secondly the increase in life expectancy (fig. 2 & 5) (Christensen et al., 2009). Thus we face two future problems. Firstly, the increase in the cost of caring for the elderly population and secondly our decreased ability to pay it (fig. 5). 1. Fertility  Fertility has decreased significantly during the last century. During the height of the Baby Boom, in 1957, the total fertility rate in the US was 3.7 births per woman. By 2014 that number had decreased to 2 children (data from: www.gapminder.org). In figure 4 it can be seen that the number of children per woman has decreased in virtually all countries between 1957 and 2015. A consequence of this lower birth rate is that the dependency ratio is increasing. For example, in Japan there were 9.3 people under 20 for every person over 65 in 1950. By 2025 this is expected to decrease to only 0.59 people under 20 for each person over 65 (Gems, 2011). 2.    Life expectancy Life expectancy has increased linearly since 1840 (fig. 5; Oeppen and Vaupel, 2002; Christensen et al., 2009). In the 20th century the life expectancy in the US has increased by over 30 years. This increase has been mostly driven by a decrease in child mortality and a decrease in death from infectious diseases due to improvements in sanitation, nutrition, housing, clean drinking water, and the development of vaccines and antibiotics (Frieden, 2015). However, life expectancy is also increasing for people at advanced ages (fig. 2; Bell and Miller, 2002; Organisation for Economic Co-operation and Development, 2009). In fact, life expectancy at age 65 and 80 has increased more strongly than life expectancy at birth (Health & Consumer protection Directorate-General, 2007). The increase in life expectancy in older ages stems from decreases in the mortality of age-related diseases. For example, the mortality from cardiovascular disease has been decreasing since the 1960s in the US (fig. 6; National Heart, Lung, and Blood Institute, 2013). The data displayed in figure 6 are for the non-age adjusted death rate, however the age-adjusted death rates shows a similar decline. The decline is happening in both genders, in people of different ethnicity and has been observed in other countries as well (data see: National Heart, Lung, and Blood Institute, 2013). Between 1950 and 2010, the age-adjusted death rates decreased for cancer, cerebrovascular diseases, heart disease, and diabetes (fig. 7; Hunter and Reddy, 2013). Superimposed on the aging of the population is the obesity epidemic. The obesity epidemic also increases the number of people suffering from non-communicable diseases such as cardiovascular disease, type 2 diabetes mellitus, osteoarthritis, and various cancers (Rubenstein, 2005). Although, as Victor Björk argued in a Longevity Reporter article last year, the ‘aging epidemic’ is a much larger problem than the obesity epidemic (Björk, 2015). Some demographers have warned that the increased rates of obesity could slow, stop or even reverse the increase in life expectancy. Others argue that the increase in mortality from obesity could be offset by a decline in smoking rates (Preston et al., 2014). Shockingly, the preliminary analysis of the mortality records for 2015 in the US shows that the crude death rate was higher in 2015 than in 2014. The age-adjusted death rate was higher in three quarters in 2015 compared to 2014 and lower in another quarter. The crude and age-adjusted death rates increased for several age-related (among others Alzheimer’s disease, Parkinson’s disease, and stroke) and age-independent (among others homicide, drug overdose, and suicide) causes of death (National Center for Health Statistics, 2016). A recent PNAS paper found that all-cause mortality had steadily increased between 1999 and 2013 in middle-aged Caucasian woman and males in the US. In contrast, during the same time period the mortality rates of Hispanic men and women had declined. The increased mortality in Caucasians was mainly attributed to an increase in substance abuse (drug and alcohol), suicides and poisonings (Case and Deaton, 2015). Only 4.1% of the US population was over 65 years old in 1900. By the turn of the 21st century this percentage had increased to 12.4% and projections show that it will likely hit 20.6% by 2050. So in 2050 one in five people would, by today’s pension age, classify for retirement. The number of over 85 years old will increase even more, from about 1.5% of the population in 2000 to 5% in 2050 (Federal Interagency Forum on Ageing-Related Statistics, 2008 table 1b). Figure 8 shows the global projected future increases in various age groups between 2010 and 2050. The 100+ age group is projected to increase 10-fold between 2010 and 2050 (National Institute on Aging, 2011). 3.    Healthy life expectancy   How much of the lifespan is spent in good health? To answer this question we must first establish what it means to be healthy. According to the World Health Organization health is “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity” (World Health Organization, 1946). This is a bit of a too stringent definition as few people ever experience a state of complete physical, mental and social well-being. Several tools are used to investigate the health of the elderly population including self-reported health, activities of daily living (ADLs), instrumental activities of daily living (IADLs), number of doctor or hospital visits, disability-free years, and healthy life years. Between 1991 and 2011 the life expectancy of people over age 65 in England increased by 4.5 years for men and 3.6 years for women. The number of years free from any cognitive impairment as well as the years spent in excellent or good self-perceived health increased by a similar extent while the increase in the number of disability-free years was smaller (fig. 9; Jagger et al., 2016). The smaller increase in disability-free years was mostly due to an increase in mild disabilities. As we already mentioned above, the number of people over 65 who have one or more limitations in performing daily tasks has decreased in the US between the years 1992 and 2005 (Federal Interagency Forum on Ageing-Related Statistics, 2008). In a French study the researchers found that cognitive function was better in a sample of elderly tested in 2008-2009 versus between 1991 and 1997 (de Rotrou et al., 2013). The HALE study found a trend towards better physical functioning (measured by disability and the need for help) in similar age groups over time (Äijänseppä et al., 2005). Finally, in 2005, 42% of people over 65 in the US had one or more limitations performing daily tasks compared to 49% in 1992 (Federal Interagency Forum on Ageing-Related Statistics, 2008). 4.    Cost of aging   4.1. Cost of medical treatment for age-related diseases   More than 200 diseases show an age-related exponential increase in mortality and among these are the top causes of death in the US (Alexey Moskalev, personal communication). In addition to this aging also leads to a decrease in many physiological functions including loss of bone density, loss of muscle strength, loss of hearing, loss of visual acuity, decline in immune function (immunosenescence), decrease in reaction times, decreased oxygen uptake and exchange, and many more (Bulterijs et al. Physiological Aging Database, unpublished).     Aging leads to a decrease in muscle strength, balance, and more rapid exhaustion after exercise (Guralnik et al., 1996). Together these factors lead to an impairment in the ability to execute normal activities of daily living (cooking food, going to the shop, washing oneself,…). The economic costs of several age-related diseases has been explored in our article series “Our aging world” (Bulterijs, 2015). In figure 10 we have summarized some of the worrying statistics on the cost of some of the most common age-related diseases. For example, the estimated annual worldwide cost of dementia is larger than the current US defence budget (Bulterijs, 2015). The annual direct cost from cardiovascular disease (CVD) is projected to increase from $273 billion in 2010 to an astounding $818 billion in 2030 in the US alone. On top of direct medical costs the American Heart Association predicts that the cost from CVD due to loss of productivity will increase from $172 billion in 2010 to $276 billion in 2030 (Heidenreich et al., 2011). Hence the total cost from CVD in the US is projected to be over $1 trillion or about a seventeenth of the GDP of the US (http://data.worldbank.org/).   Many people may believe that age-related diseases are mostly a problem of high income countries but this is not correct. For example, two thirds of dementia patients live in low- and middle-income countries (LMICs) (Prince et al., 2008) and three fourths of global deaths from CVD occur in LMICs (Gaziano et al., 2010).   Multimorbidity, the coexistence of two or more chronic diseases, increases with age from 50% in people aged 65 years to 81.5% for people over 85 (Salive, 2013). The consequence of this is that treating individual diseases increasingly becomes harder as the patient ages and that the cost of care for that patient becomes ever more expensive (Butler et al., 2008; Goldman et al., 2013).   Medicare spending has been projected to increase from 3.7% of GDP in 2012 to 7.3% in 2050 (Congressional Budget Office, 2012). Total medical spending between 1992 and 1996 was $37,581 during the last year of life (Hoover et al., 2002). A lot of this money is spent on futile invasive procedures that may not even lengthen the lifespan of the patient (Gawande, 2014). Would it not be better if this money was spend in the preceding years and decades on preventive medicine and geroprotective interventions? 4.2. Cost of assistance and care   The second contributing factor to the cost of aging is the cost of assistance with daily activities (such as in-home care), rehabilitation after injury or surgery, and institutionalized care (such as residential care facilities and nursing homes). In 2010, 9.3% of people aged 85 or older were residents of a nursing home and an additional 3.7% lived in residential care facilities or other institutions. The annual state and federal Medicaid spending for long-term care in the US increased from less than $30 billion in 1995 to $60 billion in 2013 and is expected to increase to $100 billion by 2023. The annual per patient cost of care services ranged from around $20,000 for home health aide to $90,000 for a private nursing home room (Congressional Budget Office, 2013). It is clear that the postponement of institutionalized care will result in significant financial savings for individuals and society. 4.3.Cost of pensions   While life expectancy has significantly increased over the last century, the age of retirement is, in most countries, below that of the first retirement program created by Otto von Bismarck in 1889 (https://www.ssa.gov/history/age65.html). Retirement age was set at 70 years but later in 1916 this age was lowered to 65. The average effective retirement age in OECD countries was just under 65 for men and 63 for women. The effective retirement age is highest in Korea (73 years for men and 70.6 years for women) and the lowest for men in France (59.4 years) and Slovak Republic for women (58.2 years) (http://www.oecd.org/)  In 2010 for the first time social security in the United States ran a deficit and it is highly unlikely that they will ever run a surplus again. Although official numbers still show a surplus of $69 billion in 2012, this is attributed to creative accounting. The reality is that social security ran a deficit of $148.1 billion in 2012 (Zhavoronkov, 2013). America’s private pension plans are equally unprepared to deal with the future increase in the number of retired people (Lowenstein, 2008).             The economic benefit from delayed aging Goldman et al. (2013) created a model to investigate the economic impact of delayed aging (20% decline in intrinsic mortality) versus a status quo or a disease-specific (cancer and heart disease) delayed scenario. The authors used a model in which delayed aging causes a compression of morbidity (see later). It was found that delaying aging would lead to a slower growth of the number of elderly people with disabilities and will reduce per capita Medicare spending compared to either the status quo or the specific disease delay model. Due to the resulting increase in the elderly population in the delayed aging scenario the total Medicare spending was increased. However, this increase could potentially be offset by an increase in the number of years in which the elderly population could make contributions to the economy. David Kekich has argued that we should consider the elderly as an asset rather than a burden (Mykytyn, 2010). Furthermore, it should be noted that health also creates wealth because healthy people have more energy and work more efficiently than sick people (Arrison, 2011).       Elderly workers have accumulated decades-worth of experience in their field of work. Elderly salespeople have built up relationships with clients. Supervisors have over the years fine-tuned their leadership skills. Engineers have learned creative ways to fix problems from previous experiences. Replacing them with young workers means a loss in productivity as younger workers need training and have to learn how tasks can be accomplished in the most efficient manner. Dependent on the nature of the job, training a new employee can be quite expensive. Increasing the pension age thus can help businesses to keep their most experienced workers and reduce the cost of training new staff. Elderly workers who have often worked a long period of time in the company are also more loyal and will less likely quit the job, resulting in the waste of the training expenses.       It has been estimated that delaying the onset of Alzheimer’s disease by 5 years would annually save the US health care $40 billion. The prevention of urine incontinence would result in an annual saving of $10.8 billion in the US (Balin, 1993).   Our current paradigm of treating individual diseases separately is doomed to fail as the successful treatment of a single disease is followed by the appearance of another (Holliday, 1995). An alternative strategy that is believed to have a large future potential to improve health is the slowing down of the aging process. The underlying hypothesis is that delaying the rate of biological aging will simultaneously delay the onset and progression of a wide array of non-communicable diseases (Finkel, 2005; Bulterijs, 2012; Kaeberlein et al., 2015; Longo et al., 2015). The validity of this hypothesis is demonstrated by the fact that experimental interventions in aging often simultaneously delay multiple diseases in laboratory animals (Niccoli and Partridge, 2012). Furthermore, centenarians, a human model of deccelerated aging, often have a delayed onset of age-related disease and disabilities (Lipton et al., 2010). Morbidity patterns in centenarians have been classified in three groups, (i) Survivors, (ii) Delayers, and (iii) Escapers. Survivors are those who developed an age-related disease before the age of 80 and yet continued to live on (24% of males and 43% of females). Delayers are those who delayed the onset of age-related disease to at least age 80 (44% of males and 42% of females). And finally escapers are those who reached age 100 without any diagnosed age-related disease (32% of males and 15% of females) (Evert et al., 2003). Thus surprisingly, almost one third of male centenarians had remained free from age-related disease until their 100th birthday! When we look at supercentenarians, people over 110 years of age, the number of escapers is even higher. 69% of supercentenarians remained free of age-related disease until at least their 100th birthday (Andersen et al., 2012). Many supercentenarians also remain living independently until very high ages. For example, the current oldest person in Europe, Emma Morano still lives at home with only partial assistance at the age of 116 (http://www.longevityreporter.org/blog/2015/12/12/life-at-116-meeting-a-supercentenarian).   Eliminating single diseases will have little effect on life expectancy. A 50-year old women in the United States in 1985 could expect to live another 31 years. Curing cancer would add about 3 extra years as would curing heart disease. Curing cancer, heart disease, stroke and diabetes would have a combined effect on life expectancy of 25 extra years. In contrast slowing down aging by the same extend as calorie restriction does in mice would allow a 50 year old women to live 63 more years (Miller, 2002; Martin et al., 2003).   S. Jay Olshansky and colleagues coined the term the ‘longevity dividend’ to describe the combined social, economic, and health benefits achieved from a slowing of the rate of aging (Olshansky et al., 2007; Olshansky, 2016). The need to extend healthspan has been called a “keystone for a sustainable Europe” (Health & Consumer protection Directorate-General, 2007). Different life extension scenarios     At least seven different possible scenarios for life extension can be imagined (fig. 11; de Grey, 2004; Kennedy and Pennypacker, 2014; Hansen and Kennedy, 2016). First lifespan can be extended without a chance in the age of onset for morbidity (not depicted). This is the least preferred scenario as it would result in a longer period of life spend in bad health and an increase in health care costs. An example of this scenario would be an 80-year old whose life is prolonged by a few days or weeks by aggressive medical treatment in the intensive care unit (ICU). The second scenario is the compressed morbidity scenario. In this scenario the healthspan is extended and in addition the period between morbidity onset and death is shortened (Fries, 1980). A third scenario is one in which the healthspan is extended thus resulting in a delayed onset of morbidity and an increased lifespan. This is the type of scenario that has most often been observed in lifespan studies in model organisms (see below). Finally there’s the rejuvenation scenario made famous by the biogerontologist Aubrey de Grey. In this scenario one (or multiple repetitive) rejuvenation treatment(s) would restore physiological function (decreases in morbidity) (de Grey, 2004).   Which of these theoretical scenarios is most likely? The extended lifespan without a delay in the onset of morbidity scenario is often feared by lay people when confronted with news on life extension. The long term critic of longevity research Francis Fukuyama has termed this “a global nursing home” (Fukuyama, 2002). Aubrey de Grey counters these criticisms and describes them as the “Tithonus Error” after the Greek mythological story of Tithonus, a Trojan warrior, who was made immortal but not eternally young by Zeus and hence kept becoming ever frailer for eternity (de Grey, 2008). While certain interventions such as the ICU example from above demonstrate that lifespan can be extended without an extension of healthspan, the lifespan extension obtained is likely going to be small. Most animal studies observe that interventions that extend lifespan also extended the healthspan. For example, calorie restriction, the oldest method known to extend lifespan, has protective effects against cancer, type 2 diabetes mellitus, cardiovascular disease, Alzheimer’s disease, and preserves muscle strength (Bulterijs, 2012). Furthermore, we observe a compression of morbidity in centenarians and supercentenarians (Andersen et al., 2012; Lipton et al., 2010). Although, a paper published last year in PNAS suggests that lifespan and healthspan can be uncoupled in roundworms (Bansal et al., 2015). Another example, comes from a study from a few years ago in which authors show that the drug lamotrigine extends lifespan of fruit flies but reduces their locomotor activity (the authors consider locomotor activity to be a measure of health but of course this can be questioned) (Avanesian et al., 2010). Conversely, there are also interventions that seem to improve healthspan without improving lifespan. For example, exercise has been shown to improve healthspan in mice without extending their life span (Garcia-Valles et al., 2013). Finally, some life extension treatments extend lifespan and positively impact several measures of health but not every single one. An example of that is Neff et al. (2013) who found that rapamycin improved some age-related phenotypes (such as exploratory activity and learning and memory) while not improving others (such as grip strength, glomerulosclerosis, and lens transparency). Of course, it may not come as a surprise that a single intervention is not able to delay all age-related phenotypes. People thinking that it would often come from the perspective that aging is a programmed system with master regulators and that the treatment is going to influence these master regulators and hence prevent every single age-related phenotype simultaneously. In contrast if we see aging as the result of a balance between the accumulation of various kinds of molecular and cellular damage and the opposing force of longevity assurance mechanisms (such as antioxidant enzymes, glutathione transferases, chaperones, autophagy, proteosomal degradation,…) (Johnson et al., 1999) then it becomes clear that single interventions are unlikely to affect all age-related phenotypes simultaneously.   When we compare the mortality curve from the US population at the start of the twentieth century with the one from the start of the twenty-first century we see a clear “rectangularization” (fig. 12; Arias, 2007). The number of centenarians is increasing. When studying the data from supercentenarians it seems that the mean lifespan is increasing without a corresponding increase in maximum lifespan leading to a so called “rectangularization” of the survival curve (Coles, 2004). The mortality suddenly sharply increases at age 114, a phenomenon that has sometimes been called the “death wall” (Victor Björk, personal communication). Interestingly, L. Stephen Coles has autopsied nine supercentenarians (people over 110-years of age) and found that seven died from transthyretin amyloidosis (Coles, 2011; Coles and Young, 2012). Excitingly, recently it was found that the FDA-approved drug tolcapone inhibits not only amyloidosis of mutant transthyretin but also of WT transthyretin (Sant’Anna et al., 2016). Thus it begs the question if we will be able to extend the lifespan of supercentenarians with this drug and hence overcome the “death wall”? Future prospects on increasing health- and lifespan     In the last two decades a remarkable progress has been made in enhancing the longevity of various experimental model organisms (fig. 13). The first genetic mutation to ever increase lifespan was discovered in the lab of Tom Johnson in 1988. The discovery happened in the roundworm C. elegans in which a mutation in the age-1 gene was able to extend its lifespan by 40% (Friedman and Johnson, 1988). Later another mutation in the same gene resulted in the longest life span extension observed so far, a nearly 10-fold extension (Ayyadevara et al., 2008). Over 200 genes are currently known to extend the lifespan of worms when manipulated (Henderson et al., 2006). In mice progress has been less extreme and only a few dozen mutations (knock-outs or knock-ins) are known to extend lifespan. In addition to this the lifespan of mice has also been extended by gene therapy (Bernardes de Jesus et al., 2012) and by the insertion of an artificial genetic construct that instructs senescent cells to commit suicide (Baker et al., 2011, 2016). To the best of our knowledge the number of chemical compounds that have shown to extend lifespan in some experimental model numbers around 1,000 compounds. Two compounds stand out, rapamycin and metformin. Rapamycin stands out because it was successful in extending the lifespan of heterogeneous mice when started in middle age and because at least nine studies so far have confirmed its life extending effects (Harrison et al., 2009).  Very recently a double-blind trial of rapamycin was started in dogs (dogagingproject.com). In the first phase of the trial 24 middle-aged dogs were given either rapamycin or a placebo three times a week for 10 weeks and their heart function was investigated by echocardiograms. At the end of the 10 week study period the heart function of the dogs on rapamycin had remained either unchanged or had improved (Brown, 2016). Now these researchers are planning a longer-term study with a larger cohort of dogs. In this phase the researchers also plan to investigate the effects of rapamycin treatment on various age-related parameters such as cognitive function, heart function, immunity and cancer incidence. The life extending effects of metformin were first discovered by the lab of Vladimir Anisimov in 1980 and have since been replicated in multiple mice and rat strains (Bulterijs, 2011; Martin-Montalvo et al., 2013). Metformin is the first life extension drug to go into FDA-approved human clinical testing (read our article about it here). Finally, a brief word on the expected cost of biomedical interventions in aging. Some treatments such as gene therapy and cell therapy will likely carry hefty price tags while other treatments such as metformin would be extremely affordable. The cost of metformin is only cents per dose, and the cost of geroprotective interventions will likely be more than offset by the increased period in which people are able to contribute to the economy and the delaying in the need for expensive assisted care (such as nursing home care. Conclusion   In conclusion, the earth is experiencing a demographic transition. There were already 27 countries (26 in Europe + Japan) in the year 2000 in which the number of people over 65 year old was higher than those under 15 (United Nations Population Division, 2002). The increase in the number of elderly people will place a strain on the health care, institutionalized care, and pension expenditures. While a decrease in fertility has led to a decrease in the number of young people who contribute to economic activities. However, interventions that decelerate the rate of aging have the potential to greatly improve human health and actually create economic benefits by keeping the most experienced workers longer in the workforce and reducing the need for long-term care. Without such interventions we likely will experience a severe economic regression as government and private insurance are unable to pay the health expenses and retirement benefits.     References   Äijänseppä S, Notkola I-L, Tijhuis M, van Staveren W, Kromhout D, Nissinen A (2005). Physical functioning in elderly Europeans: 10 year changes in the north and south: the HALE project. J Epidemiol Community Health 59: 413-419.   Andersen SL, Sebastiani P, Dworkis DA, Feldman L, Perls TT (2012). Health span approximates life span among many supercentenarians: compression of morbidity at the approximate limit of life span. J Gerontol A Biol Med Sci 67A: 395-405.   Arias E (2007). National Vital Statistics Reports: United States life tables, 2004. Centers for Disease Control and Prevention vol. 56, no. 9. Online available at: http://www.cdc.gov/nchs/data/nvsr/nvsr56/nvsr56_09.pdf   Arrison S (2011). 100 plus: How the coming age of longevity will change everything, from careers and relationships to family and faith. Basic Books, New York.   Avanesian A, Khodayari B, Felgner JS, Jafari M (2010). Lamotrigine extends lifespan but compromises health span in Drosophila melanogaster. Biogerontology 11(1): 45-52.   Ayyadevara S, Alla R, Thaden JJ, Shmookler Reis RJ (2008). Remarkable longevity and stress resistance of nematode PI3K-null mutants. Aging Cell 7(1): 13-22.   Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM (2011). Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479: 232–236.   Baker DJ, Childs BG, Durik M, Wijers ME, Sieben CJ, Zhong J, Saltness RA, Jeganathan KB, Verzosa GC, Pezeshki A, Khazaie K, Miller JD,van Deursen JM (2016). Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature 530(7589): 184-189.   Balin AK (1993). Testimony in support of biomedical aging research. AGE 16: 75-76.   Bansal A, Zhu LJ, Yen K, Tissenbaum HA (2015). Uncoupling lifespan and healthspan in Caenorhabditis elegans longevity mutants. Proc Natl Acad Sci USA 112(3): E277-E286.   Bell FC, Miller ML (2002). Life tables for the United States Social security Area 1900-2100. SSA Pub. No. 11-11536. Online available at: https://www.ssa.gov/oact/NOTES/pdf_studies/study116.pdf   Björk VCE (2016). Why focusing on the obesity epidemic distracts us from the aging epidemic. Longevity Reporter. Online available at: http://www.longevityreporter.org/blog/2015/10/31/why-focusing-on-the-obesity-epidemic-distracts-us-from-the-aging-epidemic   Brown KV (2016). This scientist wants your dog to live forever. Fusion. Available at: http://fusion.net/story/298806/dog-aging-rapamycin-study-kaeberlein/     Bernardes de Jesus B, Vera E, Schneeberger K, Tejera AM, Ayuso E, Bosch F, Blasco MA (2012). Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 4(8): 691-704.   Bulterijs S (2011). Metformin as a geroprotector. Rejuvenation Res 14: 469-482.   Bulterijs S (2012). The future of longevity. Pan European Networks Science Technology 05: 116-117.   Bulterijs S (2015). Our aging world. Longevity Reporter. Online available at: (1) http://www.longevityreporter.org/blog/2015/9/28/our-aging-world-the-striking-statistics-about-bone-fractures (2) http://www.longevityreporter.org/blog/2015/10/7/our-aging-world-the-striking-statistics-of-dementia (3) http://www.longevityreporter.org/blog/2015/10/9/our-aging-world-the-striking-statistics-about-cancer (4) http://www.longevityreporter.org/blog/2015/12/16/our-aging-world-the-striking-statistics-about-diabetes       Bulterijs S, Hull RS, Björk VC, Roy AG (2015). It is time to classify biological aging as a disease. Front Genet. 6: 205.   Butler RN, Miller RA, Perry D, Carnes BA, Williams TF, Cassel C, Brody J, Bernard MA, Partridge L, Kirkwood T, Martin GM, Olshansky SJ (2008). New model of health promotion and disease prevention for the 21st century. BMJ 337: a399.   Case A, Deaton A (2015). Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century. Proc Natl Acad Sci USA 112(49): 15078-15083.   Christensen K, Doblhammer G, Rau R, Vaupel JW (2009). Ageing populations: the challenges ahead. Lancet 374: 1196-1208.   Coles LS (2004). Demographics of human supercentenarians and the implications for longevity medicine. Ann N Y Acad Sci 1019: 490-495.   Coles LS (2011). Extreme longevity: Secrets of the oldest old. Presentation at the Organisation for Economic Co-operation and Development (OECD) Conference in Mexico. Powerpoint slides available at: http://www.oecd.org/finance/private-pensions/48129952.pdf   Coles LS, Young RD (2012). Supercentenarians and transthyretin amyloidosis: The next frontier of human life extension. Prev Med 54: S9-S11.   Congressional Budget Office (2012). The 2012 long-term budget outlook. Washington DC, Pub. No. 4507. Online available at: http://www.cbo.gov/sites/default/files/cbofiles/attachments/06-05-Long-Term_Budget_Outlook.pdf   Congressional Budget Office (2013). Rising demand for long-term services and supports for elderly people. Pub. No. 4240. Online available at: https://www.cbo.gov/sites/default/files/113th-congress-2013-2014/reports/44363-LTC.pdf   Evert J, Lawler E, Bogan H, Perls T (2003). Morbidity profiles of centenarians: survivors, delayers, and escapers. J Gerontol A Biol Sci Med Sci 58(3): 232-237.   Federal Interagency Forum on Ageing-Related Statistics (2008). Older Americans 2008. Key Indicators of Well-Being. Washington, DC: U.S. Government Printing Office. Online available at: http://www.agingstats.gov/Main_Site/Data/2008_Documents/OA_2008.pdf   Finkel T (2005). Radical medicine: treating ageing to cure disease. Nat Rev Mol Cell Biol 6: 971-976.   Frieden TR (2015). The future of public health. N Engl J Med 373: 1748-1754.   Friedman DB, Johnson TE (1988). A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118: 75-86.   Fries JF (1980). Aging, natural death, and the compression of morbidity. N Engl J Med 303: 130-135.   Frolkis VV. Aging and life-prolonging processes. Translated from Russian by Nicholas Bobrov. Springer-Verlag, Vienna, 1982.     Fukuyama F (2002). Our Posthuman Future: Consequences of the Biotechnology Revolution. Farrar, Straus and Giroux, New York.   Garcia-Valles R, Gomez-Cabrera MC, Rodriguez-Mañas L, Garcia-Garcia FJ, Diaz A, Noguera I, Olaso-Gonzalez G, Viña J (2013). Life-long spontaneous exercise does not prolong lifespan but improves health span in mice. Longev Healthspan 2(1): 14.     Gawande A (2014). Being mortal: Medicine and what matters in the end. Metropolitan Books, New York.   Gaziano TA, Bitton A, Anand S, Abrahams-Gessel S, Murphy A (2010). Growing epidemic of coronary heart disease in low- and middle-income countries. Curr Probl Cardiol 35(2): 72-115.   Gems D (2011). Aging: to treat, or not to treat? The possibility of treating aging is not just an idle fantasy. Am Sci 99(4): 278-280.     Goldman DP, Cutler D, Rowe JW, Michaud PC, Sullivan J, Peneva D, Olshansky SJ (2013). Substantial health and economic returns from delayed aging may warrant a new focus for medical research.Health Aff (Millwood) 32: 1698-1705.   de Grey ADNJ (2004). Escape velocity: Why the prospect of extreme human life extension matters now. PLoS Biol 2(6): e187.   de Grey ADNJ (2008). Combating the Tithonus Error: What Works? Rejuvenation Res 11(4): 713-715.   Guralnik JM, Fried LP, Salive ME (1996). Disability as a Public Health Outcome in the Aging Population. Annu Rev Public Health 17: 25-46.   Hansen M, Kennedy BK (2016). Does longer lifespan mean longer healthspan? Trends Cell Biol [Epub ahead of print].   Harrison DE et al. (2009). Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460(7253): 392-395.   Health & Consumer protection Directorate-General (2007). Healthy ageing: keystone for a sustainable Europe – EU health policy in the context of demographic change. Online available at: http://ec.europa.eu/health/archive/ph_information/indicators/docs/healthy_ageing_en.pdf   Heidenreich PA et al. (2011). Forecasting the Future of Cardiovascular Disease in the United States: A Policy Statement From the American Heart Association. Circ 123: 933-944.   Henderson ST, Rae SL, Johnson TE (2006). Dissecting the processes of aging using the nematode Caenorhabditis elegans. In: Masoro EJ, Austad SN. The biology of aging, Sixth edition. Academic Press, Burlington, MA.   Holliday R (1995). Understanding ageing. Cambridge University Press, Cambridge.   Hoover DR, Crystal S, Kumar R, Sambamoorthi U, Cantor JC (2002). Medical Expenditures during the Last Year of Life: Findings from the 1992–1996 Medicare Current Beneficiary Survey. Health Serv Res 37(6): 1625-1642.   Hunter DJ, Reddy KS (2013). Noncommunicable diseases. N Engl J Med 369: 1336-1343.   Jagger C, Matthews FE, Wohland P, Fouweather T, Stephan BCM, Arthur A, Brayne C (2016). A comparison of health expectancies over two decades in England: results of the Cognitive Function and Ageing Study I and II. The Lancet 387(10020): 779-786.     Johnson FB, Sinclair DA, Guarente L (1999). Molecular biology of aging. Cell 96(2): 291-302.   Kennedy BK, Pennypacker JK (2014). Drugs that modulate aging: The promising yet difficult path ahead. Transl Res 163(5): 456-465.   Longo VD, Antebi A, Bartke A, Barzilai N, Brown-Borg HM, Caruso C, Curiel TJ, de Cabo R, Franceschi C, Gems D, Ingram DK, Johnson TE, Kennedy BK, Kenyon C, Klein S, Kopchick JJ, Lepperdinger G, Madeo F, Mirisola MG, Mitchell JR, Passarino G, Rudolph KL, Sedivy JM, Shadel GS, Sinclair DA, Spindler SR, Suh Y, Vijg J, Vinciguerra M, Fontana L (2015). Interventions to slow aging in humans: Are we ready? Aging Cell 14: 497-510.   López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013). The hallmarks of aging. Cell 153: 1194-1217.   Lowenstein R (2008). While America Aged: How Pension Debts Ruined General Motors, Stopped the NYC Subways, Bankrupted San Diego, and Loom as the Next Financial Crisis. Penguin Books Ltd., London.   Martin GM, LaMarco K, Strauss E, Kelner KL (2003). Research on aging: the end of the beginning. Science 299: 1340-1341.   Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin MJ, Schwab M, Pollak M, Zhang Y, Yu Y, Becker KG, Bohr VA, Ingram DK, Sinclair DA, Wolf NS, Spindler SR, Bernier M, de Cabo R (2013). Metformin improves healthspan and lifespan in mice. Nat Commun 4: 2192.   Miller RA (2002). Extending life: scientific prospects and political obstacles. Millback Quarterly 80: 155-174.   Mykytyn CE (2010). Analyzing predictions: An anthropological view of anti-aging futures. In: Fahy GM, Coles LS, Harris SB (eds.). The future of aging: Pathways to human life extension. Springer, New York.   National Center for Health Statistics (2016). Quarterly provisional estimates for selected causes of death: United States, 2014–Quarter 4, 2015. National Vital Statistics System, Vital Statistics Rapid Release Program.   National Heart, Lung, and Blood Institute (2013). Fact book: Fiscal year 2012. Online available at: http://www.nhlbi.nih.gov/about/documents/factbook/2012   Neff F, Flores-Dominguez D, Ryan DP, Horsch M, Schröder S, Adler T, Afonso LC, Aguilar-Pimentel JA, Becker L, Garrett L, Hans W, Hettich MM, Holtmeier R, Hölter SM, Moreth K, Prehn C, Puk O, Rácz I, Rathkolb B, Rozman J, Naton B, Ordemann R, Adamski J, Beckers J, Bekeredjian R, Busch DH, Ehninger G, Graw J, Höfler H, Klingenspor M, Klopstock T, Ollert M, Stypmann J, Wolf E, Wurst W, Zimmer A, Fuchs H, Gailus-Durner V, Hrabe de Angelis M, Ehninger D (2013). Rapamycin extends murine lifespan but has limited effects on aging. J Clin Invest 123(8): 3272-3291.   National Institute on Aging (2011). Global health and aging. NIH publication No 11-7737. Online available at: https://www.nia.nih.gov/research/publication/global-health-and-aging/overview   Niccoli T, Partridge L (2012). Ageing as a risk factor for disease. Curr Biol 22: R741-R752.   Organisation for Economic Co-operation and Development (2009). Health at a glance: OECD indicators. Online available at: http://www.oecd-ilibrary.org/social-issues-migration-health/health-at-a-glance-2009_health_glance-2009-en.   Oeppen J, Vaupel JW (2002). Demography. Broken limits to life expectancy. Science 296(5570): 1029-1031.   Olshansky SJ, Perry D, Miller RA, and Butler RN (2007). Pursuing the longevity dividend: Scientific goals for an aging world. Ann NY Acad Sci 1114: 11-13.   Olshansky SJ (2016). Articulating the Case for the Longevity Dividend. Cold Spring Harb Perspect Med 6(2): a025940.   Preston SH, Stokes A, Mehta NK, Cao B (2014). Projecting the effect of changes in smoking and obesity on future life expectancy in the United States. Demography 51(1): 27-49.   Prince M, Acosta D, Albanese E, Arizaga R, Ferri CP, Guerra M, Huang Y, Jacob KS, Jimenez-Velazquez IZ, Rodriguez JL, Salas A, Sosa AL, Sousa R, Uwakwa R, Van Der Poel R, Williams J, Wortmann M (2008). Ageing and dementia in low and middle income countries – Using research to engage with public and policy makers. Int Rev Psychiatr 20(4): 332-343.   de Rotrou J, Wu Y-H, Mabire J-B, Moulin F, de Jong LW, Rigaud A-S, Hanon O, Vidal J-S (2013). Does Cognitive Function Increase over Time in the Healthy Elderly? PLoS ONE 8(11): e78646.   Rubenstein AH (2005). Obesity: A Modern Epidemic. Trans Am Clin Climatol Assoc 116: 103-113.   Salive ME (2013). Multimorbidity in Older Adults. Epidemiol Rev 35(1): 75-83.   Sant’Anna R, Gallego P, Robinson LZ, Pereira-Henriques A, Ferreira N, Pinheiro F, Esperante S, Pallares I, Huer tas O, Rosário Almeida M, Reixach N, Insa R, Velazquez-Campoy A, Reverter D, Reig N, Ventura S (2016). Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity. Nat Commun 7: 10787.   Sjöberg JS, Bulterijs S (2009). Characteristics, formation, and pathophysiology of glucosepane: a major protein cross-link. Rejuvenation Res 12(2): 137-148.   Strehler BL (1962). Time, cells and aging. Academic Press, New York.   United Nations Population Division (2002). World population ageing: 1950-2050. United Nations Publications, New York. Online available at: http://www.un.org/esa/population/publications/worldageing19502050/   Vaupel JW (2010). Biodemography of human ageing. Nature 464: 536-542.   World Health Organization (1946). Preamble to the Constitution of the World Health Organization. New York, NY: WHO.   Zhavoronkov A (2013). The ageless generation: How advances in biomedicine will transform the global economy. Palgrave MacMillan, New York.